Placental P-glycoprotein: Role in disposition of medications administered during pregnancy

Abstract

The placenta supports fetal growth and regulates the bio-distribution of substances between the maternal and fetal circulation. Active efflux transporters in the placental apical membrane are involved in placental elimination of compounds and thus fetal protection. The goal of this investigation was to evaluate developmental and genetic influences on expression and activity of the placental efflux transporter P-glycoprotein (P-gp) and its role in regulating the placental distribution of medications used during pregnancy. P-gp expression and transport activity were defined in brush border membrane vesicles prepared from human placenta of various gestational ages. The expression and transport activity of P-gp declined progressively throughout gestation. There was a lack of correlation between P-gp expression and activity in individual samples, which may be influenced by three polymorphisms in the Multidrug Resistance 1 (MDR1) gene encoding P-gp associated with decreased protein expression yet increased transport activity in these patients. P-gp was found to transport medications used in the treatment of conditions during pregnancy: namely opiate dependence, cigarette smoking, and gestational diabetes. Considerations of P-gp involvement in placental distribution must therefore be taken into account when planning therapy of these conditions during pregnancy. Finally, the need for an in vivo animal model for studying placental P-gp transport of investigational drugs during pregnancy led to our identification of the baboon as a comparable model to human placental P-gp expression and activity. Future studies should investigate gene-wide analysis of functional MDR1 variants and the in vivo role of placental P-gp in the disposition of medications used during pregnancy.